Insomnia is a common sleep disturbance that affects the quantity or quality of sleep. Insomnia may be acute (one to several nights) or chronic (months to years). The symptoms of insomnia are typically described as an inability to fall asleep (sleep onset insomnia) or remain asleep (sleep maintenance insomnia). In some instances, insomnia is associated with other medical conditions, such as anxiety and depression, or with use of certain medications. According to the National Sleep Foundation's Sleep in America Poll 2005, insomnia was a concern because the effects of sleep deprivation were reported to decrease the quality of life of the individual, and in some cases, compromise the safety and normal functioning of the individual in the workplace and while driving.
The current treatment of insomnia will vary depending on the etiology, nature, and severity of symptoms, and may include the use of pharmacologic agents. These agents typically are sedative compounds that include, but are not limited to: barbiturates, benzodiazepines, non-benzodiazepine sedatives (i.e. imidazopyridine class (zolpidem), pyrazolopyrimidine class (zaleplon) and pyrrolopyrazine class (eszopiclone)), GABAA receptor agonists, antihistamines, orexin receptor agonists, phenothiazines, melatonin, and melatonin MT1 and MT2 receptor agonists. As used herein, the terms “sedative”, “hypnotic”, “sedative hypnotic” and similar words or phrases are to be understood to be synonymous and refer to the ability to induce sleep.
Currently, oral nonbenzodiazepines such as Ambien® tablets (zolpidem tartrate) (Sanofi-Aventis, Bridgewater, N.J.), Lunesta® tablets (eszopiclone) (Sepracor, Marlborough, Mass.), and Sonata® capsules (zaleplon) (King Pharmaceuticals, Bristol, Tenn.).
Other nonbenzodiazepine treatments, all orally administered, which may include melatonin (OTC) and the melatonin receptor MT1/MT2 agonist Rozerem® tablets (ramelteon) (Takeda Pharmaceutical Co., Ltd., Osaka, Japan), are frequently prescribed for sleep disturbances.
Developmental compounds include the nonbenzodiazepine GABAA agonist, Indiplon (Neurocrine, San Diego, Calif.) and those with novel receptor activity such as HY10275 which is a dual-acting H1/5-HT2A compound (Hypnion/Lilly, Lexington, Mass.) and almorexant, an orexin receptor antagonist (Actelion/GSK, Basel, Switzerland). These newer therapies minimize or avoid undesirable side effects typical of the GABAA agonists, such as memory impairment and dependence and abuse potential, tolerance and rebound insomnia.
All of these compounds are administered orally, and therefore can take from 1-2 hours to onset of therapeutic effects. Food or alcohol intake can significantly enhance or retard the therapeutic effects or time to onset. Because of the long time to onsets, the long duration of effects and the variability with GI loading, these therapies must be administered on a specific schedule hours before retiring for a normal sleep period. Because oral bioavailability can be low, relatively high doses are required to achieve and sustain systemic circulation concentrations sufficiently high to be effective, particularly for sleep maintenance. Such high dosage levels, combined with the long half lives of elimination typical of these compounds, result in long washout periods which can prolong residual sedation into normal waking hours.
Given the importance of the sedative-hypnotics in treating insomnia, an alternative to oral administration would be desirable to administer sedative hypnotics by means that would have rapid onset and could be administered just before retiring for normal sleep period. Devices for generating aerosols of sedative-hypnotic drugs for inhalation would enable rapid onset because therapeutically effective concentrations can be achieved rapidly by pulmonary administration. Additionally inhalation avoids interference from food or drink that is found with oral administration. Inhalation also bypasses first pass metabolism and results in higher bioavailability for small molecules such as the sedative-hypnotics. Therefore lower doses can be used to rapidly achieve therapeutic concentrations in systemic circulation in as fast as 2-3 minutes. The lower doses minimize side effects and residual sedation at the end of sleep period.